Inhibitors of human immunodeficiency virus (HIV) protease have been approved for use in the treatment of HIV infection for several years. A particularly effective HIV integrase inhibitor is N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1-{[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino}ethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide, also known as raltegravir and its pharmaceutically acceptable salts such as raltegravir potassium. Raltegravir is represented by the following structure.

Polymorphism is defined as “the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline forms of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules”. Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph. It is therefore important to investigate all solid forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning calorimetry (DSC) and Infrared spectrometry (IR).
Solvent medium and mode of crystallization play very important role in obtaining a crystalline form over the other.
Raltegravir can exist in different polymorphic forms, which differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
WO Patent Publication No. 03/035077 disclosed N-substituted 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamides and pharmaceutically acceptable salts thereof. Processes for the preparations of raltegravir and related compounds were disclosed in WO Patent No. 03/035077. According to WO Patent No. 03/035077, raltegravir is prepared by reacting 5-methyl-1,3,4-oxadiazole-2-carboxylic acid with 2-(1-amino -1-methylethyl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide in acetonitrile in presence of triethyl amine and N,N-dimethylformamide.
WO Patent Publication No. 2006/060712 disclosed two crystalline forms of raltegravir potassium and processes for their preparation. The Publication described the formation of two crystalline forms of raltegravir potassium, which were designated raltegravir potassium salt of crystalline anhydrous Form 1 and hydrated Form 2.
According to the '712 patent publication, crystalline anhydrous form 1 of raltegravir potassium salt (characterized by an X-ray powder diffraction pattern having peaks expressed as 2θ at about 5.9, 12.5, 20.0, 20.6 and 25.6 degrees and further characterized by an differential scanning calorimetry exhibiting a single endotherm with a peak temperature of about 279 deg C.) can be prepared by crystallization of raltegravir potassium from mixing an aqueous solution of a potassium base with a mixture comprising raltegravir, water and alcohol to form a basic solution of raltegravir and filtering the solution. The resulting solution was seeded to provide the crystalline potassium salt of raltegravir.
According to the '712 patent publication, crystalline hydrated form 2 of raltegravir potassium salt (characterized by an X-ray powder diffraction pattern having peaks expressed as 2θ at about 7.9, 13.8, 15.7, 24.5 and 31.5 degrees and further characterized by an differential scanning calorimetry exhibiting two broad endotherms with peak temperatures of about 146 deg C. and 239 deg C. and a third sharp endotherm with a peak temperature of about 276 deg C.) can be prepared by crystallization of raltegravir potassium from solid potassium hydroxide and raltegravir were added to acetone, and the resulting solution was sonicated for several minutes until a precipitate formed. Then the resulting suction was filtered to dryness.
We have discovered that raltegravir can be prepared in well-defined and consistently reproducible amorphous form and crystalline form.
One object of the present invention is to provide a process for the preparation of amorphous form of raltegravir potassium and pharmaceutical compositions comprising it.
Another object of the present invention is to provide a novel crystalline form of raltegravir potassium and a process for preparing it and pharmaceutical compositions comprising it.